Permax (Pergolide Mesylate)

PERMAX®

Draxis Health

Pergolide Mesylate

Dopamine Agonist

Action And Clinical Pharmacology: Pergolide mesylate, a synthetic ergot derivative, is a dopamine receptor agonist at both D1 and D2 receptor sites.

In Parkinson’s disease, pergolide is believed to exert its therapeutic effect by directly stimulating postsynaptic dopamine receptors in the corpus striatum. In addition, pergolide suppresses the secretion of prolactin, causes a transient increase in serum concentration of growth hormone and a decrease in serum concentration of luteinizing hormone.

To-date only very limited pharmacokinetic data are available. Following oral administration of 4-pergolide, radioactivity in plasma appeared after 15 to 30 minutes, peaked at 1 to 2 hours, and was barely detectable after 96 hours. Radioactivity was eliminated as pergolide metabolites in urine (55%), in feces (40%) and in breath (5%). No unchanged pergolide was detected in excreta. At least 10 radioactive metabolites have been isolated including N-despropylpergolide, pergolide sulfoxide and pergolide sulfone. The latter 2 metabolites are dopamine agonists in animals. The other detected metabolites have not been identified and it is not known whether they are pharmacologically active.

Pergolide is approximately 90% bound to plasma proteins. This extent of protein binding may be important to consider when pergolide is coadministered with other drugs known to affect protein binding.

Indications And Clinical Uses: As an adjunct to levodopa (usually with a peripheral decarboxylase inhibitor) in the symptomatic management of Parkinson’s disease.

Evidence to support the efficacy of pergolide was obtained in a double-blind, placebo-controlled multicenter study which enrolled patients with mild to moderate Parkinson’s disease who were intolerant to l-dopa/carbidopa treatment as manifested by moderate to severe dyskinesia and/or on-off phenomena.

Pergolide has not been assessed in the treatment of newly diagnosed patients or as the sole medication in Parkinson’s disease.

Contra-Indications: Patients who are hypersensitive to this drug or other ergot derivatives.

Manufacturers’ Warnings In Clinical States: Hypotension: Pergolide may cause syncope or hypotension (i.e., a fall in systolic blood pressure to less than 100 mmHg). It is therefore important to warn patients of the risk, to begin therapy with low doses, and to increase the dosage in carefully adjusted increments over a period of several weeks (see Dosage).

Syncope or excessive hypotension were observed in patients on pergolide therapy, especially during initiation of treatment. Episodes of moderate hypotension also occurred. With gradual dosage titration, tolerance to hypotension usually develops.

Care should be exercised when administering pergolide concomitantly with antihypertensive agents or other medications known to lower blood pressure.

Occupational Hazards: Patients receiving pergolide should be cautioned with regard to engaging in activities requiring rapid and precise responses, such as driving an automobile or operating machinery.

Hallucinosis: In controlled trials, pergolide with levodopa caused hallucinosis in about 14% of patients as opposed to 3% taking placebo with levodopa. This was of sufficient severity to cause discontinuation of treatment in about 3% of those enrolled; tolerance to this untoward effect was not observed.

Fatalities: In the placebo-controlled trial, 2 of 187 patients treated with placebo died as compared with 1 of 189 patients treated with pergolide. In the latter group, 3 additional patients died who continued on pergolide beyond the controlled phase of the study. Of the 2 299 patients treated with pergolide in premarketing studies 143 died while on the drug or shortly after discontinuing the drug. The patient population under evaluation was elderly, ill, and at high risk for death. It seems unlikely that pergolide played any role in these deaths, but the possibility that pergolide shortens survival of patients cannot be excluded with absolute certainty.

Precautions: General: The abrupt discontinuation of pergolide in patients receiving it chronically as an adjunct to levodopa may precipitate the onset of hallucinations and confusion; these may occur within a span of several days. Discontinuation of pergolide should be undertaken gradually whenever possible, even if the patient is to remain on levodopa.

A symptom complex resembling the neuroleptic malignant syndrome (NMS), characterized by elevated body temperature, muscular rigidity, altered consciousness, and autonomic instability, has been reported in antiparkinsonian therapy. Therefore, patients should be observed carefully when the dosage of pergolide is reduced abruptly or discontinued.

The administration of pergolide to patients receiving levodopa may cause and/or exacerbate pre-existing dyskinesia.

Cardiovascular Effects: Pergolide has not been systematically evaluated in patients with heart disease. In the multicenter clinical trial, patients with heart disease, i.e., recent angina pectoris, decompensated heart failure (New York Scale III or IV), myocardial infarction within the last 12 months, or any arrhythmia requiring antiarrhythmic therapy at the time of the study or within 12 months prior to the study were excluded. Since there is only limited experience with pergolide in these patients, pergolide should be administered only if in the judgement of the physician the potential benefits clearly outweigh the potential risks.

In a study comparing pergolide and placebo, patients taking pergolide were found to have significantly more episodes of atrial premature contractions (APCs) and sinus tachycardia.

Drug Interactions: Dopamine antagonists such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide ordinarily should not be administered concurrently with pergolide (a dopamine agonist) because these agents may diminish the effectiveness of pergolide.

Because pergolide is approximately 90% bound by plasma proteins, caution should be exercised if pergolide is coadministered with other drugs known to affect protein binding.

Pregnancy: In teratology studies performed in mice and rabbits, there was no evidence of harm to the fetus due to pergolide. There are however, no adequate and well-controlled studies in pregnant women. In a small number of women who received pergolide for endocrine disorders, there were 33 pregnancies that resulted in healthy babies and 6 pregnancies that resulted in congenital abnormalities (3 major, 3 minor); a causal relationship has not been established. Because human data are limited and because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only, if in the opinion of the treating physician, the possible benefit to the patient outweighs the potential risks to the fetus.

Lactation: It is not known whether pergolide is excreted in human milk. The pharmacologic action of pergolide suggests that it may interfere with lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions to pergolide in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Children: Safety and effectiveness in children have not been established.

Adverse Reactions: Commonly Observed: The most commonly observed adverse events associated with the use of pergolide are: nervous system complaints, including dyskinesia, dizziness, hallucinations, somnolence, and insomnia; gastrointestinal complaints, including nausea, constipation, diarrhea and dyspepsia; cardiovascular complaints, including postural hypotension, and respiratory system complaints, including rhinitis.

Adverse Reactions Resulting in Discontinuation of Treatment: Twenty-seven percent of approximately 1 200 patients, receiving pergolide for treatment of Parkinson’s disease in premarketing clinical trials in the U.S. and Canada, discontinued treatment due to adverse reactions. Events most often causing discontinuation were related to the nervous system (15.5%), primarily hallucinations (7.8%) and confusion (1.8%).

Incidence of Adverse Reactions in Controlled Clinical Trials: Table I enumerates adverse events that occurred at a frequency of 1% or more among pergolide treated patients who participated in the double-blind controlled clinical trial comparing pergolide with placebo. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevail in clinical trials. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.

Certain adverse experiences (e.g., dyskinesias, hallucinations) are frequently observed in patients receiving levodopa pergolide and/or other dopamine agonists. These are dose related and tend to improve with reduction of the dosage of levodopa or of pergolide. Hallucinations may infrequently persist after discontinuation of pergolide.

Postural hypotension and nausea are most frequently reported during the initial titration phase.

Abnormalities in laboratory tests may include elevations of AST, ALT, alkaline phosphatase and urea nitrogen.

Other Events Observed During the Premarketing Evaluation of Pergolide: This section reports event frequencies of adverse reactions that occurred in approximately 1 700 patients who took multiple doses of pergolide in premarketing studies worldwide. The conditions and duration of exposure to pergolide varied greatly, involving well-controlled studies as well as experience in open and uncontrolled clinical settings. In the absence of appropriate controls in some of the studies, a causal relationship to pergolide treatment cannot be determined.

The following definitions of frequency are used: Frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1 000 patients; rare events are those occurring in less than 1/1 000 patients.

Body as a Whole System: Frequent: headache, asthenia, injury accident, abdominal pain, chest pain, back pain, fever, flu syndrome, neck pain. Infrequent: enlarged abdomen, malaise, neoplasm, hernia, pelvic pain, facial edema, chills, sepsis, cellulitis, moniliasis, abscess, jaw pain, hypothermia. Rare: acute abdominal syndrome, LE syndrome, erythromelalgia.

Nervous System: Frequent: hallucinations, psychosis, paranoid reaction, personality disorder, akinesia, dyskinesia, choreoathetosis, dystonia, tremor, abnormal gait, incoordination, speech disorders, dizziness, confusion, depression, anxiety, somnolence, insomnia, abnormal dreams, amnesia. Infrequent: neuropathy, hypertonia, delusions, convulsion, libido increase, euphoria, emotional lability, libido decrease, akathisia, vertigo, neuralgia, myoclonus, coma, apathy, paralysis, neurosis, hyperkinesia, ataxia, acute brain syndrome, torticollis, meningitis, manic reaction, hypokinesia, hostility, agitation. Rare: stupor, neuritis, intracranial hypertension, hemiplegia, facial paralysis.

Gastrointestinal: Frequent: nausea, vomiting, constipation, dyspepsia, anorexia, diarrhea, dry mouth, dysphagia. Infrequent: flatulence, abnormal liver function tests, increased appetite, salivary gland enlargement, thirst, gastroenteritis, gastritis, rectal disorder, peridontal abscess, intestinal obstruction, nausea and vomiting, gingivitis, esophagitis, cholelithiasis, tooth caries, hepatitis, stomach ulcer, melena, hepatomegaly, hematemesis, eructation. Rare: sialadenitis, peptic ulcer, pancreatitis, colitis, cholecystitis, aphthous stomatitis. Cardiovascular: Frequent: postural hypotension, hypotension, syncope, hypertension, palpitations, arrhythmia, vasodilatation, congestive heart failure. Infrequent: myocardial infarct, tachycardia, cardiac arrest, abnormal ECG, angina pectoris, thrombophlebitis, bradycardia, ventricular extrasystoles, cerebrovascular accident, ventricular tachycardia, cerebral ischemia, atrial fibrillation, varicose vein, pulmonary embolus, AV block, shock. Rare: vasculitis, pulmonary hypertension, pericarditis, migraine, heart block, cerebral hemorrhage.

Respiratory: Frequent: rhinitis, dyspnea, pneumonia, pharyngitis, cough increased. Infrequent: sinusitis, bronchitis, epistaxis, voice alteration, hemoptysis, asthma, lung edema, hiccup, pleural effusion, laryngitis, emphysema, apnea. Rare: pneumothorax, lung fibrosis, larynx edema, hypoxia, hypoventilation, hyperventilation, hemothorax, carcinoma of lung.

Metabolic and Nutritional Findings: Frequent: peripheral edema, weight loss, weight gain. Infrequent: dehydration, hypokalemia, hypoglycemia, gout, hyperglycemia, iron deficiency anemia, hypercholesteremia. Rare: electrolyte imbalance, cachexia, acidosis, hyperuricemia.

Special Senses: Frequent: diplopia. Infrequent: otitis media, conjunctivitis, tinnitus, deafness, taste perversion, ear pain, eye pain, glaucoma, eye hemorrhage.

Rare: blindness, cataract, retinal detachment, retinal vascular disorder.

Musculoskeletal: Frequent: twitching, myalgia, arthralgia. Infrequent: bursitis, bone pain, tenosynovitis, myositis, bone sarcoma. Rare: osteoporosis, muscle atrophy.

Skin and Appendages: Frequent: sweating, rash. Infrequent: skin discoloration, pruritus, acne, skin ulcer, alopecia, dry skin, skin carcinoma, seborrhea, hirsutism, herpes simplex, eczema, fungal dermatitis. Rare: vesiculobullous rash, subcutaneous nodule, skin nodule, skin benign neoplasm, lichenoid dermatitis, herpes zoster.

Urogenital: Frequent: urinary tract infection, urinary frequency, urinary incontinence, prostatic disorder, dysmenorrhea, hematuria. Infrequent: dysuria, breast pain, menorrhagia, impotence, cystitis, urinary retention, menstrual disorder, abortion, vaginal hemorrhage, vaginitis, abnormal ejaculation, priapism, kidney calculus, fibrocystic breast, lactation, uterine hemorrhage, urolithiasis, salpingitis, pyuria, metrorrhagia, menopause, kidney failure, breast neoplasm. Rare: amenorrhea, bladder carcinoma, breast engorgement, epididymitis, hypogonadism, leukorrhea, nephrosis, pyelonephritis, urethral pain, uricaciduria, withdrawal bleeding.

Hemic and Lymphatic: Frequent: anemia. Infrequent: leukopenia, lymphadenopathy, leukocytosis, thrombocytopenia, petechia, megaloblastic anemia, cyanosis. Rare: purpura, lymphocytosis, eosinophilia, acute lymphoblastic leukemia.

Postmarketing Reports: Voluntary reports of adverse events temporally associated with pergolide that have been received since market introduction and which may have no causal relationship with the drug, include the following: neuroleptic malignant syndrome.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no clinical experience with massive overdosage. The largest overdose involved a young hospitalized adult patient who was not being treated with pergolide but who intentionally took 60 mg of pergolide. He experienced vomiting, hypotension and agitation. Another patient receiving a daily dosage of 7 mg of pergolide, unintentionally took 19 mg/day for 3 days, after which his vital signs were normal but he experienced severe hallucinations. Within 36 hours of resumption of the prescribed dosage level, the hallucinations stopped. One patient unintentionally took 14 mg/day for 23 days instead of her prescribed 1.4 mg/day dosage. She experienced severe involuntary movements and tingling in her arms and legs. Another patient who inadvertently received 7 mg instead of the prescribed 0.7 mg experienced palpitations, hypotension and ventricular extrasystoles. The highest total daily dose (prescribed for several patients with refractory Parkinson’s disease) has exceeded 30 mg.

Animal studies indicate that the manifestations of overdosage in man might include nausea, vomiting, convulsions, decreased blood pressure, and CNS stimulation.

Management of overdosage may require supportive measures to maintain arterial blood pressure. Cardiac function should be monitored; an antiarrhythmic agent may be necessary. If signs of CNS stimulation are present, a phenothiazine or butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs has not been assessed in reversing the effects of overdose. There is no experience with dialysis or hemoperfusion; these procedures are unlikely to be of benefit.

Dosage And Administration: Administration of pergolide should be initiated with a single daily dose of 0.05 mg for the first 2 days. The dose should then be gradually increased by 0.1 to 0.15 mg/day every third day over the next 12 days of therapy. The dosage may then be increased by 0.25 mg/day every third day until an optimal dosage is achieved.

Pergolide is usually administered in divided doses 3 times/day. During dosage titration, the dosage of levodopa/carbidopa may be cautiously decreased.

Since rapid escalation of the drug causes severe adverse reactions, it is recommended that a slow increase of pergolide be combined with a concomitant, gradual and limited reduction of levodopa dosage.

In clinical studies, the mean therapeutic dose of pergolide was 3 mg/day. The average concurrent levodopa/carbidopa daily dosage (expressed as levodopa) was approximately 650 mg/day. The safety of pergolide at doses above 5 mg/day has not been systematically evaluated.

Availability And Storage: 0.05 mg : Each ivory-colored, modified rectangle-shaped tablet, scored and engraved with the company logo and Identi-code 4131, contains: pergolide mesylate 0.05 mg. Nonmedicinal ingredients: croscarmellose sodium, iron oxide yellow, lactose, l-methionine, magnesium stearate and povidone. Gluten- and tartrazine-free. Amber HDPE bottles of 30.

0.25 mg : Each green, modified rectangle-shaped tablet, scored and engraved with the company logo and Identi-code 4133, contains: pergolide mesylate 0.25 mg. Nonmedicinal ingredients: croscarmellose sodium, FD&C blue No. 2, iron oxide yellow, lactose, magnesium stearate and povidone. Gluten- and tartrazine-free. Amber HDPE bottles of 100.

1 mg : Each pink-colored, modified rectangle-shaped tablet, scored and engraved with the company logo and Identi-code 4135, contains: pergolide mesylate 1 mg. Nonmedicinal ingredients: croscarmellose sodium, iron oxide red pure, lactose, magnesium stearate and povidone. Gluten- and tartrazine-free. Amber HDPE bottles of 100.

Store at room temperature.

PERMAX® Draxis Health Pergolide Mesylate Dopamine Agonist

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